Age increased the cancer‐specific mortality risk of thyroid cancer with lung metastasis

To investigate the relationship between age and cancer‐specific mortality in thyroid cancer (TC) with lung‐metastasis.


| INTRODUCTION
Thyroid cancer (TC) is one of the most common endocrine tumours, and its incidence has been increasing over the past four decades. 1 At present, TC has become the sixth most common malignancy for women in the United States. 2,3 TC is divided into two categories according to the cell origin: endoderm-derived follicular cells and neural crest-derived C-cells. 4 The former includes differentiated TC (DTC) (papillary TC [PTC], follicular TC [FTC] and poorly differentiated TC], and anaplastic TC (ATC). Meanwhile, the latter category is also known as medullary TC (MTC). 4 DTC accounts for approximately 90% of all TC types. 4,5 In terms of clinical characteristics, DTC is usually indolent, while ATC is the most aggressive variant, accounting for approximately 40% of all deaths from TC. 5,6 The most common metastatic site of TC is the lung, 7 followed by the bone, and occasionally the brain and liver. 8,9 DTC is a unique malignancy because the age at diagnosis can be an independent risk factor for prognosis. 10,11 In 2016, the American Joint Committee on Cancer (AJCC) released the eighth edition of the AJCC/TNM cancer staging system. According to this edition, the age cut-off used for DTC staging was increased from 45 to 55 years at diagnosis. 12 Indeed, several studies had shown that age over 55 years was an important risk factor for metastasis and prognosis of DTC, 13 as well as for the effect of radioactive iodine (RAI) therapy. 14 However, in TC patients who were over 55 years with distant metastases, there was no further risk stratification according to age to clarify its impact on TC-specific mortality. As such, our study aimed to investigate the relationship between age and prognosis in TC patients who were over 55 years with lung metastasis at diagnosis and identify more precise risk stratification for this subset of patients, offering personalized treatment therapy to ensure an optimal response.

| Data source and study subjects
This retrospective study utilized data from the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER). 15  cording to the 7th AJCC staging system), tumour size and distant metastases. Radiotherapy information was categorized as radiation beam or radioactive implants, radioisotopes or radiation beam plus isotopes or implants, none or refused, and unknown. 16 Patients were divided into five groups based on age: ≤55 years, >55 but ≤65 years, >65 but ≤75 years, >75 but ≤85 years and >85 years.
The relationship between age and TC-specific mortality was analysed.
All data were obtained from the SEER public database. We received official permission to access these data for noncommercial use. Therefore, this study was exempted from a review by the ethics committee of Shanghai Tenth People's Hospital. All authors have signed the author declaration form.

| Statistical analysis
The clinical characteristics were statistically described. Differences in TC-specific survival time were compared among patients from different groups using Kaplan-Meier analysis and the log-rank test. The impact of age on TC-specific survival was assessed using Cox proportional hazards regression and was presented as hazard ratios (HRs) with 95% confidence intervals (CIs). Statistical significance was defined as a two-tailed p-value of less than .05. All data were analysed using the Statistical Package for Social Science version 25 (SPSS Inc). Note: According to the American Joint Committee on Cancer (AJCC) Staging Manual 7th edition, lymph node category was classified into five groups as follows: No regional lymph node metastasis (N0); metastases to Level VI (pretracheal, paratracheal and prelaryngeal/delphian lymph nodes) (N1a); metastasis to unilateral, bilateral or contralateral cervical (Levels Ⅰ, Ⅱ, Ⅲ

| Demographic and clinical characteristics
, Ⅳ or Ⅴ) or retropharyngeal or superior mediastinal lymph nodes (Level Ⅶ) (N1b); metastasis to regional lymph nodes but not otherwise specified (N1NOS); and regional lymph nodes cannot be assessed (NX).

| Kaplan-Meier analyses of TC-specific survival of TC patients with lung metastasis
In TC patients with distant metastases, TC-specific survival curves decreased significantly with increased age (log-rank p < .001; Figure 1A), and the survival curve of patients over 85 years showed an obvious decline with the worst prognosis.
Similar results were observed in PTC ( Figure 1B) and FTC ( Figure 1C). There were no significant survival differences among all age groups in ATC patients ( Figure 1D). In TC patients with lung metastasis, the TC-specific survival curves also decreased significantly with increased age (logrank p < .001; Figure 2A). Similar results were observed in PTC ( Figure 2B) and FTC ( Figure 2C), but not in ATC patients ( Figure 2D).
The survival curve of patients over 85 years showed a sharp decrease and similar trends were also observed when we further divided patients into four groups (>70 but ≤75 years, >75 but ≤80 years, >80 but ≤85 years and >85 years; Figure S1A-C). Still, advanced age had no significant impact on the survival of ATC patients ( Figure S1D).

| DISCUSSION
In the present study, we demonstrated that the TC-specific mortality rates were increased with age in patients with lung metastasis, especially in patients over 85 years of age. However, since ATC was the most aggressive subtype with the worst prognosis, age has no significant impact on ATC-specific mortality. 17 TC was one of the most common endocrine tumours, and its variants had different prognoses due to various reasons. 17,18 It was also a special type of malignancy because a patient's age at diagnosis could be an important risk factor for prognosis. 11 As early as 2009, a previous study pointed out that advanced age was related to poor prognosis. 10 The eighth edition of the AJCC/TNM cancer staging manual changed the age cut-off from 45 to 55 years for the DTC prognostic staging system. 12 DTC patients who were over 55 years and developed distant metastases at diagnosis were considered to be in Stage IVB, 12 and had the worst prognosis.
Ito et al. 13 found that age over 55 years was an independent risk factor for lung recurrence in a group of PTC patients without initial distant metastasis. Furthermore, it was also the strongest predictor of cancer-related death by a 10 years follow-up. Another study also found that in DTC patients with lung metastasis, age over 45 years was an independent risk factor for disease progression. 19 Sabra et al. 20 14,22 ; second, due to ageing, a decline in immune system functions and an increase in all-cause mortality may also be contributed to the poor prognosis of TC. 23 In addition to age, BRAF V600E mutation was also an important risk factor for poor prognosis in TC patients. 24  could be of particular use. The guidelines recommended CT or FDG-PET imaging for DTC patients with high risk who had elevated Tg (generally >10 ng/ml) or rising Tg antibodies. 28 Herein, we thought that for elderly patients with elevated Tg or Tg antibodies levels, CT or FDG-PET screening could be used as a more common tool for early detection of lung metastasis. Moreover, more radical treatment strategies can be adopted for elderly patients with TC and distant metastases. Seminal studies assessing the role of targeted therapy such as mitogen-activated protein kinase/extracellular signal-regulated kinase inhibitors to enhance radioiodine uptake in RAI refractory TC patients had shown promising results. 5,29,30 In vitro and in vivo studies had also identified new tyrosine kinase inhibitors which could enhance endogenous sodium iodide symporter expression and increase radioiodine uptake. 31 In addition, immunotherapy could also be considered to improve their prognosis. 32

| CONCLUSIONS
In conclusion, TC-specific mortality was increased with age in patients with lung metastasis. For elderly TC patients, CT or FDG-PET screening may be of special use in the early detection of lung metastasis, leading to a more precise evaluation of the prognosis and development of more personalized treatment strategies.